Presentation of peptide antigens to T cells by major histocompatibility complex (MHC) class I and class II molecules has been a central paradigm in modem immunology. Recent evidence has established that nonMHC-encoded CDI proteins comprise a novel lineage of antigen-presenting molecules, distinct from MHC proteins. Unlike MHC molecules, which bind short peptide in their antigen-binding groove for presentation to either CD4+ or CD8+ T cells bearing alphabeta T cell receptors, CDI molecules appear to accommodate microbial lipid and glycolipid antigens in their hydrophobic cavity for presentation to a variety of T cells, including double negative alphabeta and gammadelta T cells and CD8+ alphabeta T cells. Mycobacterium tuberculosis (M.tb)-specific, CD1-restricted T cells recognize and kill M.tb-infected dendritic cells, implying their potential role in clearing microbial infection. Epidermal Langerhans cells (LCs) are epidermis-resident dendritic cells that mediate a pivotal role in skin immunity. They express MHC class II molecules abundantly and activate either alloreactive or peptide antigenspecific CD4+ T cells. LCs are also characterized by their abundant expression of CD1a, an isoform of the human CD1 family, and our preliminary results indicated that CDla expressed on LCs indeed functioned as antigen-presenting molecules capable of binding microbial lipid antigens and presenting them to CD8+ T cells. We hypothesize that LCs may play important roles in normal and pathological skin by initiating CD1-mediated immune responses, including autoreactive responses. Thus, in this proposal, we will (1) define the capability of LCs to present CD1-restricted lipid antigens to T cells, (2) characterize the function of LC-reactive, CD1-restricted T cells, including autoreactive T cells, and (3) determine the precursor frequency of such T cells in peripheral blood of healthy subjects and patients with psoriasis, a disease of the skin with an inflammatory infiltrate in the dermis and epidermis, including CD8+ T cells. These studies will clarify the ability of LCs to activate T cells via a novel antigen presentation pathway mediated by CD1, and provide a new insight into the understanding of inflammatory skin diseases such as psoriasis.